Long term follow-up in GAMT deficiency – Correlation of therapy regimen, biochemical and in vivo brain proton MR spectroscopy data

Abstract: GAMT deficiency is a rare autosomal recessive disease within the group of cerebral creatine deficiency syndromes. Cerebral creatine depletion and accumulation of guanidinoacetate (GAA) lead to clinical presentation with intellectual disability, seizures, speech disturbances and movement disorders. Treatment consists of daily creatine supplementation to increase cerebral creatine, reduction of arginine intake and supplementation of ornithine for reduction of toxic GAA levels. This study represents the first long-term follow-up over a period of 14 years, with detailed clinical data, biochemical and multimodal neuroimaging findings. Developmental milestones, brain MRI, quantitative single voxel 1H magnetic resonance spectroscopy (MRS) and biochemical analyses were assessed. The results reveal insights into the dose dependent effects of creatine/ornithine supplementation and expand the phenotypic spectrum of GAMT deficiency. Of note, the creatine concentrations, which were regularly monitored over a long follow-up period, increased significantly over time, but did not reach age matched control ranges. Our patient is the second reported to show normal neurocognitive outcome after an initial delay, stressing the importance of early diagnosis and treatment initiation.

Parent Summary: This study reports a 14-year follow-up of a patient with GAMT deficiency, a rare inherited disorder causing low brain creatine and buildup of toxic guanidinoacetate. The condition leads to intellectual disability, seizures, speech problems, and movement issues. Treatment includes daily creatine supplements to raise brain creatine levels, reducing arginine intake, and adding ornithine to lower toxic guanidinoacetate. Over time, creatine levels in the patient’s brain increased significantly but remained below normal for their age. The patient showed near-normal neurocognitive development after early diagnosis and treatment, highlighting the importance of starting therapy as soon as possible. This long-term study provides valuable data on treatment effects and broadens understanding of GAMT deficiency symptoms.

Link to article: https://www.sciencedirect.com/science/article/pii/S2214426924000065?via%3Dihub

PubMed:  https://pubmed.ncbi.nlm.nih.gov/38469086/

Authors: Lara M. Marten, Ralph Krätzner, Gajja S. Salomons, Matilde Fernandez Ojeda, Peter Dechent, Jutta Gärtner, Peter Huppke, Steffi Dreha-Kulaczewski

Key Terms: GAMT, Clinical Study, MRS, Diagnostic, Supplements, Pediatric Patient, Adult Patient, Male Patient